Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival

Cell. 2007 Nov 2;131(3):596-610. doi: 10.1016/j.cell.2007.08.036.


Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • CHO Cells
  • Calcium Signaling* / drug effects
  • Cell Survival / drug effects
  • Cricetinae
  • Cricetulus
  • Cytosol / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Intracellular Membranes / metabolism*
  • Ligands
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Molecular Chaperones / metabolism*
  • Protein Binding / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • RNA, Small Interfering / metabolism
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*
  • Sigma-1 Receptor
  • Thermodynamics
  • Up-Regulation / genetics


  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ligands
  • Molecular Chaperones
  • RNA, Small Interfering
  • Receptors, sigma
  • Adenosine Triphosphate